The effectiveness of the COVID-19 vaccines in the prevention of post-COVID conditions in children and adolescents: a systematic literature review and meta-analysis

Objective: We performed a systematic literature review and meta-analysis on the effectiveness of coronavirus disease 2019 (COVID-19) vaccination against post-COVID conditions (long COVID) in the pediatric population. Design: Systematic literature review/meta-analysis. Methods: We searched PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from December 1, 2019, to August 14, 2023, for studies evaluating the COVID-19 vaccine effectiveness against post-COVID conditions among vaccinated individuals < 21 years old who received at least 1 dose of COVID-19 vaccine. A post-COVID condition was defined as any symptom that was present 4 or more weeks after COVID-19 infection. We calculated the pooled diagnostic odds ratio (DOR) (95% CI) for post-COVID conditions between vaccinated and unvaccinated individuals. Results: Eight studies with 23,995 individuals evaluated the effect of vaccination on post-COVID conditions, of which 5 observational studies were included in the meta-analysis. The prevalence of children who did not receive COVID-19 vaccines ranged from 65% to 97%. The pooled prevalence of post-COVID conditions was 21.3% among those unvaccinated and 20.3% among those vaccinated at least once. The pooled DOR for post-COVID conditions among individuals vaccinated with at least 1 dose and those vaccinated with 2 doses were 1.07 (95% CI, 0.77–1.49) and 0.82 (95% CI, 0.63–1.08), respectively. Conclusions: A significant proportion of children and adolescents were unvaccinated, and the prevalence of post-COVID conditions was higher than reported in adults. While vaccination did not appear protective, conclusions were limited by the lack of randomized trials and selection bias inherent in observational studies.


Background
The ongoing global battle against the coronavirus disease 2019 (COVID-19) pandemic has seen remarkable progress in vaccine development and distribution. 1,2As adults and high-risk populations receive their COVID-19 vaccinations, the focus has increasingly turned toward vaccinating children and adolescents.While much attention has rightfully been placed on preventing COVID-19 infections in these age groups, it is equally critical to consider the potential impact of vaccination on preventing post-COVID conditions, often referred to as long COVID.
Post-COVID conditions encompass a wide spectrum of persistent health problems that can afflict individuals for weeks, months, or even longer after the initial COVID-19 infection. 3ccording to a published systematic literature review, the prevalence of post-COVID conditions in the pediatric population varies remarkably from 1.6% to 70%. 4 Long COVID can negatively affect daily function and school attendance. 3,4esearch has demonstrated the efficacy, safety, and tolerability of COVID-19 vaccines in the pediatric population. 5Beyond preventing infection, COVID-19 vaccines also can prevent severe outcomes, including emergency department or urgent care visits, hospitalizations, and even death. 6,7Furthermore, vaccination can allow more children to attend school. 5s COVID-19 vaccine campaigns have progressed, more children are getting vaccinated.Vaccine effectiveness (VE) assesses the level of protection provided by COVID-19 vaccines against specific conditions. 2While VE against post-COVID conditions among the adult population is estimated to be 30%, 8 VE against post-COVID conditions among the pediatric population is still unknown.Therefore, our objective was to conduct a systematic literature review on the effectiveness of COVID-19 vaccines to prevent post-COVID conditions in children and adolescents, and we pooled the results of published studies to allow for more precise effectiveness estimates.

Systematic literature review and inclusion and exclusion criteria
This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement 9 and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines 10 and was registered on Prospero (https://www.crd.york.ac.uk/PROSPERO/) on June 9, 2023 (registration number CRD42023456888).Institutional Review Board approval was not required.Inclusion criteria for studies in this systematic review were as follows: original research manuscripts, published in peer-reviewed scientific journals, involved vaccinated (at least 1 dose of COVID-19 vaccines [mRNA or vectorial or inactivated viral vaccine]) and unvaccinated individuals, evaluated the long-term effectiveness of the COVID-19 vaccine, evaluated the pediatric population (individuals < 21 years old), and observational study design.Post-COVID condition (also known as long COVID) was defined as a wide range of health symptoms that are present 4 or more weeks after COVID-19 infection. 3The literature search included studies from December 1, 2019, to August 14, 2023.Editorials, commentaries, reviews, study protocols, and studies in the adult population were excluded.Studies without a comparison between vaccinated and unvaccinated individuals (or other vaccinated control groups) were also excluded.

Search strategy
We performed literature searches in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase (Elsevier Platform), Cochrane Central Register of Controlled Trials, Scopus (which includes EMBASE abstracts), and Web of Science.The entire search strategy is described in Supplementary Appendix 1.After applying the exclusion criteria, we reviewed 30 articles, of which 8 met the inclusion criteria and were included in the systematic literature review (Figure 1).

Data abstraction and quality assessment
Titles and abstracts of all articles were screened to assess whether they met the inclusion criteria.Abstract screening was performed by 2 reviewers (MCG and ARM).Of 7 independent reviewers (ARM, GYC, IP, MCG, MKH, TK, and VL), 2 independently abstracted data for each article using a standardized abstraction form.Reviewers resolved disagreements by consensus.
The reviewers abstracted data on study design, population and location, study period (months) and calendar time, demographic and characteristics of participants, and the types of COVID-19 vaccine administered if available.Post-COVID conditions were considered the primary outcome to calculate VE after at least 1 dose of a COVID-19 vaccine.Eight corresponding authors were contacted for additional information, and 2 were able to provide additional information regarding the number of individuals with and without post-COVID conditions in both vaccinated and unvaccinated groups. 11,12The risk of bias was assessed using the Downs and Black scale. 13Reviewers answered all original questions from this scale except for question #27 (a single item on the Power subscale scored 0 to 5), which was changed to a yes or no.Two authors performed component quality analysis independently, reviewed all inconsistent assessments, and resolved disagreements by consensus. 14

Statistical analysis
To perform a meta-analysis on the extracted data, we calculated the pooled diagnostic odds ratio (DOR) for post-COVID conditions between vaccinated (received at least 1 dose of a COVID-19 vaccine) and unvaccinated individuals.We performed stratified analyses by the timing of the COVID-19 vaccine (ie, those with COVID-19 vaccines before or after COVID-19 diagnosis and those with COVID-19 vaccines before COVID-19 diagnosis) and between those vaccinated with 2 doses and unvaccinated individuals.We performed statistical analysis using R version 4.1.0with mada package version 0.5.8. 15 Analogous to the metaanalysis of the odds ratio methods for the DOR, an estimator of random-effects model following the approach of DerSimonian and Laird is provided by the mada package. 15For our meta-analysis, we used a bivariate random-effects model, adopting a similar concept of performing the diagnostic accuracy.This enabled simultaneous pooling of sensitivity and specificity with mixed-effect linear modeling while allowing for the trade-off between them. 16,17eterogeneity between studies was evaluated with I 2 estimation and the Cochran Q statistic test.Publication bias was assessed using the Egger test with R version 4.1.0with metafor package. 18
Two studies included in our review were conducted in the United Kingdom, 11,20 and 2 were conducted in Thailand. 12,22One study each was performed in Israel, 19 Italy, 24 Norway, 21 and the United States. 23All studies were performed between February 2020 and October 2022.0][21][22][23][24] Four studies evaluated VE in pediatric individuals vaccinated only before COVID-19 infection, 12,20,21,24 1 study evaluated VE for post-COVID conditions among those who were vaccinated after COVID-19 infection, 22 and 3 studies evaluated VE but did not specify the timing of the vaccine. 11,19,230][21][22][23][24] Two studies evaluated vaccinated children and adolescents with 2 doses of vaccine. 12,249,23 Each study adopted different definitions for post-COVID conditions (Table 1).Post-COVID conditions were defined as symptoms lasting more than 4 weeks in 2 studies, 19,23 more than 12 weeks in 5 studies, 12,[20][21][22]24 and more than 6 months in 1 study. 11 All sdies used at least one of the common post-COVID condition symptoms (details shown in Table 1) to make a diagnosis of a post-COVID condition.Six of the included studies did not show any benefit of COVID-19 vaccination in reducing post-COVID condition symptoms in children and adolescents.11,12,[19][20][21]24 One study showed that vaccination was protective against post-COVID-19 symptoms, 23 and 1 study did not report the benefit of COVID-19 vaccination.22 In total, 5 studies, comprising 20,325 children and adolescents, investigated post-COVID conditions among individuals who had received at least 1 dose of the COVID-19 vaccine either before or after COVID-19 infection.These studies were subsequently included in the meta-analysis (Figure 2).2,20,23,24 The pooled prevalence of post-COVID conditions was 21.3% among those who were unvaccinated and 20.3% among those who received at least 1 dose.20,23,24 Of the 5 studies, 3 evaluated post-COVID conditions in individuals who received the COVID-19 vaccine before infection (Supplementary Appendix 2).9,23 Two studies assessed post-COVID conditions for those who received 2 doses before infection (Supplementary Appendix 3).12,24 The DOR was 0.82 (95% CI, 0.63-1.08)12,24 (Table 2).Because there were no studies evaluating post-COVID conditions for those who received at least 1 dose of each specific type of COVID-19 vaccine (mRNA or viral vector or inactivated viral vaccine), we did not perform a stratified   Antimicrobial Stewardship & Healthcare Epidemiology analysis.The results of meta-analyses were homogeneous for studies evaluating post-COVID conditions in individuals who received the COVID-19 vaccine before or after COVID-19 infection (heterogeneity P = .38,I 2 = 5%), and homogenous for studies evaluating post-COVID conditions in individuals receiving vaccine only before infection (heterogeneity P = .26,I 2 = 25%), and also homogenous for studies evaluating post-COVID conditions in children who received 2 doses (heterogeneity P = .77,I 2 = 0%), respectively. There was no eidence for publication bias among the 5 studies included in the meta-analysis (P = .93).

Discussion
Our systematic literature review and meta-analysis aimed to assess the VE of COVID-19 vaccination in mitigating post-COVID conditions in children and adolescents.The prevalence of those who did not receive COVID-19 vaccines was high, ranging from 65% to 97%.The pooled prevalence of post-COVID conditions was similar between unvaccinated (21.3%) and those who received at least 1 dose (20.3%). 10,11,19,22,23This meta-analysis did not demonstrate statistically significant protection with COVID-19 vaccination against post-COVID conditions in the pediatric population.Given the limited number of studies included in this meta-analysis, each with different criteria for defining post-COVID conditions, further research is necessary to comprehensively assess VE.
The pursuit of effective vaccination strategies against COVID-19, particularly for children and adolescents, has been a crucial aspect of the global response to the pandemic. 1,7,25The low prevalence of COVID-19 vaccination among the pediatric population is a concerning issue that warrants further examination. 11,12,20,23,24Initially, COVID-19 vaccines were primarily authorized for adults, and the distribution to children and adolescents occurred later. 25Certainly, understanding parental hesitancy regarding COVID-19 vaccination for their children and adolescents is a critical aspect to consider in the context of this study. 26Additionally, acknowledging that the pediatric population was one of the last to receive COVID-19 vaccines adds complexity to the discussion.The delayed access of children and adolescents to COVID-19 vaccines might have contributed to a sense of uncertainty among parents.They may have been waiting for more data and real-world evidence of vaccine safety and efficacy in this age group before making decisions. 27The spread of misinformation and disinformation about COVID-19 vaccines has contributed to vaccine hesitancy in both adults and children. 26alse claims about vaccine safety, efficacy, and adverse events can lead parents to make uninformed decisions about vaccinating their children. 26Highlighting the potential risks of post-COVID conditions in adult populations can be a persuasive argument for vaccination. 28Parents may be more inclined to vaccinate their children if they understand the potential long-term health consequences of a COVID-19 infection, even if it is mild. 4,28oreover, the study's focus on pediatric populations highlights the need for age-specific considerations in vaccination campaigns. 7,25,29he observed wide variation in the prevalence of post-COVID conditions in pediatric populations, ranging from 1.6% to 70%, underscores the complexity of this issue, 4 possibly influenced by an individual's age, health conditions, and viral variants problems. 28,30ur previous systematic review and meta-analysis evaluating the VE against post-COVID conditions among fully vaccinated adults revealed that the pooled prevalence of post-COVID conditions was 11.8% among those who were unvaccinated and 5.3% among those individuals who were fully vaccinated. 8This present systematic review demonstrated that the pediatric population had a higher prevalence at 21% in unvaccinated and 20% in vaccinated pediatric patients.The higher prevalence of post-COVID conditions in pediatric populations compared with adults is a matter of concern and requires careful consideration.Several factors could contribute to this difference. 25,30,31Emerging variants could potentially have different effects on post-COVID conditions, and their prevalence may influence VE. 32 Prior research indicated that the Delta and Omicron variants led to fewer systemic inflammatory responses, severe illnesses, or fatalities, thereby resulting in milder long COVID symptoms compared with the original wild-type variant (Wuhan). 33,34In addition, it has been reported that the prevalence of post-COVID conditions was lower during the Omicron era than during other strains, and the prior systematic review among adults might have included more research that covered the additional newer variants. 34,35The variability in how post-COVID conditions were defined across the included studies poses a significant limitation for understanding this issue.0][21][22][23][24] This heterogeneity in definitions makes it challenging to compare results across studies and draw firm conclusions about the prevalence and impact of these conditions.While our previous meta-analysis among the adult population suggested that COVID-19 vaccines might effectively prevent post-COVID-19 conditions, 36 the present meta-analysis did not demonstrate any protective effect.There are a few potential reasons for this discrepancy.Children and adolescents have unique physiological and immunological characteristics, which may influence vaccine responses and the risk of post-COVID conditions. 25It is worth noting that there have been previous studies that have also shown limited effectiveness of vaccines in preventing post-COVID conditions. 11,12,20,24These findings suggest that the relationship between vaccination and post-COVID outcomes is complex and may vary across different age groups and populations.Moreover, the timing of vaccination concerning the COVID-19 infection may be a contributing factor.Some studies have analyzed VE when administered before COVID-19 infection, 12,20 while others have assessed outcomes when given after infection. 11,22These differences in timing may contribute to the divergent results observed in different studies.Consequently, ongoing research and monitoring of vaccine safety and effectiveness in these age groups are essential for refining vaccination strategies.
Our study had several limitations.First, there were a relatively small number of articles that met the inclusion criteria.With only 8 studies included in the systematic literature review, 11,12,[19][20][21][22][23][24] the available evidence may not represent the full spectrum of the pediatric population's experience with post-COVID conditions.All of the included studies in the meta-analysis investigating the VE in preventing post-COVID conditions employ non-randomized and different observational study designs, 11,12,20,23,24 including cohort studies 11,12,23,24 and a cross-sectional study. 20While the authors applied rigorous quality assessment criteria, the possibility of residual confounding factors and selection of bias that were not accounted for in the original studies remains.Additionally, it's important to consider that children and adolescents who were sicker, frailer, or at higher risk might have been more inclined to receive vaccinations.This potential bias is difficult to completely account for in observational studies.Second, the articles included in this systematic literature review assessed the effectiveness of various COVID-19 vaccines, including mRNA vaccines, vector vaccines, and inactivated viral vaccines.The effectiveness of these vaccines in preventing post-COVID conditions may differ, but the analysis did not stratify results by vaccine type due to data limitations.Future research should explore potential differences in the impact of different vaccine types on post-COVID outcomes.Third, the studies included in our systematic literature review were conducted in various countries, with differing healthcare systems, demographics, COVID-19 vaccination programs, and COVID-19 prevalence.The diversity in settings could affect the generalizability of the findings to other regions or populations.It is important to consider that the impact of vaccines on post-COVID conditions may vary in different contexts. 30,36Lastly, although no evidence of publication bias was found in the meta-analysis, the potential for publication bias always exists in systematic reviews.Studies with significant findings, whether positive or negative, may be more likely to be published, potentially skewing the overall assessment of VE.
In conclusion, it appears that the pediatric population may experience a higher incidence of post-COVID conditions compared with adults.The study observed that COVID-19 vaccination, whether administered before or after a COVID-19 infection, did not reduce the occurrence of post-COVID conditions associated with the circulating variants during the study period among pediatric individuals.While this article contributes to our understanding of COVID-19 VE in preventing post-COVID conditions in the pediatric population, it is crucial to acknowledge the limitations of this study.Addressing these limitations through more extensive, standardized, and regionally diverse research, along with ongoing monitoring and robust study designs, will offer a more accurate insight into the relationship between vaccination and post-COVID outcomes in children and adolescents.Such efforts are vital for refining public health strategies and mitigating the long-term health effects of the pandemic among younger populations.

Figure 1 .
Figure 1.Literature search for articles on the COVID-19 vaccine effectiveness in post-COVID conditions.

Figure 2 .
Figure 2. Forest plot of COVID-19 vaccine effectiveness among post-COVID-19 conditions in individuals who received at least 1 dose of COVID-19 vaccine before or after COVID-19 infection.Diagnostic odds ratios (DOR) were determined with the DerSimonian and Laird random-effects method.Note: CI, confidence interval.

Table 1 .
Summary of characteristics of studies included in the systematic literature review